PROJECT SUMMARY The parasitic infection schistosomiasis afflicts 200 million people worldwide and is clinically treated by a single drug, praziquantel (PZQ). Despite the fact that PZQ has served as a stalwart anthelmintic for decades, the molecular basis of action of this clinical agent is not understood. This lack of mechanistic information impedes the rational design of alternative therapeutics and is worrisome in the face of emergence of schistosome strains exhibiting refractoriness to PZQ exposure. New approaches for studying the effectors engaged by PZQ in vivo are therefore needed. In this R21 application, we advance a new approach for resolving the mechanism of action of PZQ and for establishing a novel platform for antischistosomal drug discovery. This builds on the observation that PZQ evokes a complete axis duplication during regenerating of free-living planarian flatworms yielding viable, two- headed animals with integrated nervous systems. This stark visual phenotype is interrogable by chemical and genetic (in vivo RNAi) screening in the planarian system, approaches which demonstrate that PZQ action is opposed by serotonergic (5-HT) signaling. These data advance the simple hypothesis that PZQ acts a ligand of flatworm 5-HT receptors. Here, we have established methodology to test this hypothesis and to define the pharmacophore of schistosome 5-HT receptors. As these receptors control flatworm motility, we predict agents that engage these receptors, including customized ergot derivatives, will yield novel antischistosomals. This work therefore aligns with the R21 remit for bringing a completely new approach to problems: exemplified in this case as a new model system for antiparasitic drug discovery that has potential to reveal how PZQ works, a roadblock that that has eluded definition for 30 years.